HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles

Genes & development (Impact Factor: 10.8). 03/2014; 28(8). DOI: 10.1101/gad.234468.113
Source: PubMed


Fibro-adipogenic progenitors (FAPs) are important components of the skeletal muscle regenerative environment. Whether FAPs support muscle regeneration or promote fibro-adipogenic degeneration is emerging as a key determinant in the pathogenesis of muscular diseases, including Duchenne muscular dystrophy (DMD). However, the molecular mechanism that controls FAP lineage commitment and activity is currently unknown. We show here that an HDAC-myomiR-BAF60 variant network regulates the fate of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray, genome-wide chromatin remodeling by nuclease accessibility (NA) combined with next-generation sequencing (NA-seq), small RNA sequencing (RNA-seq), and microRNA (miR) high-throughput screening (HTS) against SWI/SNF BAF60 variants revealed that HDAC inhibitors (HDACis) derepress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease. Specifically, HDAC inhibition induces two core components of the myogenic transcriptional machinery, MYOD and BAF60C, and up-regulates the myogenic miRs (myomiRs) (miR-1.2, miR-133, and miR-206), which target the alternative BAF60 variants BAF60A and BAF60B, ultimately directing promyogenic differentiation while suppressing the fibro-adipogenic phenotype. In contrast, FAPs from late stage dystrophic muscles are resistant to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the promyogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bipotency by epigenetic intervention with HDACis provides a molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles.

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Available from: Agustin Rojas-Muñoz, Apr 24, 2014
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    • " of a pro - myogenic program at the expense of the fibro - adipogenic phenotype ( Saccone et al . , 2014 ) , were strongly up - regulated in mdx / mIGF - 1 compared to mdx diaphragm . The molecular mechanisms that , in concert with environmental cues , control the identity and activity of muscle cells involve the BAF60C - based SWI / SNF complex ( Saccone et al . , 2014 ) . We observed a significant up - regulation of BAF60C in the muscle of mdx / mIGF - 1 mice compared to mdx littermates ( Figure 5E ) ."
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which the absence of dystrophin leads to progressive lethal skeletal muscle degeneration. It has been demonstrated that among genes which are important for proper muscle development and function, micro-RNAs (miRNAs) play a crucial role. Moreover, altered levels of miRNAs were found in several muscular disorders, including DMD. A specific group of miRNAs, whose expression depends on dystrophin levels and whose deregulation explains several DMD pathogenetic traits, has been identified. Here, we addressed whether the anabolic activity of mIGF-1 on dystrophic muscle is associated with modulation of microRNAs expression. We demonstrated that some microRNAs are strictly linked to the dystrophin expression and are not modulated by mIGF-1 expression. In contrast, local expression of mIGF-1 promotes the modulation of other microRNAs, such as miR-206 and miR-24, along with the modulation of muscle specific genes, which are associated with maturation of regenerating fibers and with the stabilization of the differentiated muscle phenotype. These data suggest that mIGF-1, modifying the expression of some of the active players of muscle homeostasis, is able, even in absence of dystrophin expression, to activate circuitries that confer robustness to dystrophic muscle.
    Frontiers in Aging Neuroscience 05/2015; 7. DOI:10.3389/fnagi.2015.00069 · 4.00 Impact Factor
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    • "FAP cells are known to promote the differentiation of MPCs but do not have any capability to generate muscle tissue on their own; on the contrary, they appear to be the main source of the fibrotic and adipose tissues found in pathological muscles (Uezumi et al., 2011). As such, these cells have been studied as a target for with microRNA (miRNA) treatments intended to reduce the symptoms of the DMD syndrome through the upregulation of the FAP cells myogenic programming, inducing a " compensatory regeneration " (Mozzetta et al., 2013; Saccone et al., 2014). "
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    ABSTRACT: Skeletal muscle tissue is characterized by high metabolic requirements, defined structure and high regenerative potential. As such, it constitutes an appealing platform for tissue engineering to address volumetric defects, as proven by recent works in this field. Several issues common to all engineered constructs constrain the variety of tissues that can be realized in vitro, principal among them the lack of a vascular system and the absence of reliable cell sources; as it is, the only successful tissue engineering constructs are not characterized by active function, present limited cellular survival at implantation and possess low metabolic requirements. Recently, functionally competent constructs have been engineered, with vascular structures supporting their metabolic requirements. In addition to the use of biochemical cues, physical means, mechanical stimulation and the application of electric tension have proven effective in stimulating the differentiation of cells and the maturation of the constructs; while the use of co-cultures provided fine control of cellular developments through paracrine activity. This review will provide a brief analysis of some of the most promising improvements in the field, with particular attention to the techniques that could prove easily transferable to other branches of tissue engineering.
    Frontiers in Physiology 09/2014; 5:362. DOI:10.3389/fphys.2014.00362 · 3.53 Impact Factor
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    ABSTRACT: Recent studies have revealed the contribution of fibro-adipogenic progenitors (FAPs) to the pathogenesis and progression of Duchenne Muscular Dystrophy (DMD). While FAPs direct compensatory regeneration at early stages of disease, as the disease progresses they contribute to the progressive replacement of contractile myofibers with fibrotic scars and fatty infiltration. Using the mouse model of DMD - the mdx mice - we have recently reported that FAPs mediate the ability of HDAC inhibitors (HDACi) to promote muscle regeneration and prevent fibro-adipogenic degeneration at early stages of disease. This effect is mediated by the induction of myomiRs that, in turn, target the SWI/SNF components BAF60A and B, thereby favoring the formation of BAF60C-based SWI/SNF complex, which directs the switch from the fibro-adipogenic to the myogenic lineage. Here we show direct evidence of induction of miR-206 and BAF60C, and reduction of BAF60A, in FAPs isolated from mdx muscles exposed to the HDACi Trichostatin A (TSA). We also discuss how increased expression of myomiRs in dystrophic muscles can be integrated with circulating myomiRs to provide accurate biomarkers of disease progression and response to treatment.
    01/2014; 2(1):e974969. DOI:10.4161/21675511.2014.974969
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